Abstract

Objective:We hypothesized that nebulized iloprost would improve ventilation-perfusion matching in patients with pulmonary hypertension and ARDS as reflected by an improved Pao2/Fio2 ratio and Pao2 without adversely affecting lung mechanics or systemic hemodynamics.

Methods:Patients with ARDS and pulmonary hypertension were enrolled. With constant ventilator settings, hemodynamics, airway pressures, and gas exchange measured at baseline were compared with values 30 min after administration of 10 μg nebulized iloprost, and again 30 min after a second, larger, 20 μg dose of iloprost, and then a final measurement 2 h after the second dose. The primary outcome variable was Pao2; secondary outcomes were Pao2/Fio2 ratio, mean arterial BP, and lung-compliance ventilatory equivalents for oxygen and CO2.

Conclusions:The improvement in gas exchange without any detrimental effects on pulmonary mechanics or systemic hemodynamics suggests nebulized iloprost may be a useful therapeutic agent to improve oxygenation in patients with ARDS.

Figures in this Article

ARDS is characterized by diffuse pulmonary infiltrates and severe hypoxemia.1 While ARDS can develop as a consequence of many insults, sepsis, pneumonia, aspiration, transfusion, and trauma are the most common etiologies.2 There have been many clinical trials of different therapies in ARDS over the years, but only one, the ARDSnet low tidal-volume trial, has demonstrated an improvement in survival when patients were ventilated with a low tidal volume (6 mL/kg).3

Pulmonary hypertension (PH) is common in patients with ARDS.4,5 Hypoxemia is a potent pulmonary vasoconstrictor, while acidosis, inflammatory cytokines, and intravascular thrombosis are additional factors contributing to the rise in pulmonary vascular resistance.6‐10 In addition, therapeutic maneuvers such as the application of positive end-expiratory pressure (PEEP) can also contribute to the rise in pulmonary vascular resistance.11,12 This increase is associated with worsening hypoxemia and increased ventilation perfusion (V./Q. ) mismatching and lower mixed venous oxygen saturation. Previous attempts to treat PH with systemically administered vasodilators have reduced pulmonary artery (PA) pressures but increased intrapulmonary shunting and worsened hypoxemia.13,14

Iloprost is an inhaled prostanoid that has been approved by the US Food and Drug Administration as a vasodilator for patients with pulmonary arterial hypertension (PAH). When iloprost is administered by inhalation, it acts primarily on the pulmonary vasculature with little spillover into the systemic circulation. As an inhaled agent, iloprost has the potential to act preferentially in well-ventilated regions of the lung, which would receive the highest dose of iloprost and thereby maintain or even improve V./Q. matching while reducing PAH. We showed that iloprost improves V./Q. matching, arterial Po2, and exercise tolerance in patients with COPD.15 Presumably, the local vasodilatation in well-ventilated regions of the lung increases perfusion to these areas and thereby improves V./Q. matching. Importantly, iloprost had no deleterious effect on lung mechanics as measured by spirometry.

Several studies have looked at the effect of IV and inhaled epoprostenol on oxygenation and hemodynamics in patients with ARDS, but none has examined the effects of an inhaled prostanoid on pulmonary mechanics. The purpose of this study was to examine the hypothesis that iloprost would improve gas exchange in patients with ARDS without adversely affecting systemic hemodynamics or lung mechanics. We chose to study iloprost rather than epoprostenol because this agent is approved and formulated for administration by inhalation. Furthermore, in our experience, we observed no deleterious effects with this agent in patients with obstructive lung disease. We administered escalating doses to maximize the potential improvement in oxygenation as well as to enhance our ability to detect an adverse effect on hemodynamics or lung mechanics.

Materials and Methods

Patients admitted to the medical and surgical ICUs of the OU Medical Center hospital between January 4, 2012, and July 13, 2012, were screened for the presence of ARDS and PH. PH was diagnosed by a measured mean PA pressure > 25 mm Hg with a pulmonary capillary wedge pressure ≤ 15 mm Hg, or echocardiographic evidence of PH, including a PA systolic pressure ≥ 35 mm Hg with right-sided ventricular enlargement or decreased systolic function in the presence of normal, left-sided ventricular function. All echocardiograms were read by the same experienced cardiologist who was not part of the study team. ARDS was diagnosed according to consensus conference criteria as the acute onset of diffuse pulmonary infiltrates involving at least three of four quadrants on chest radiographs, a Pao2/Fio2 ratio < 300 while on mechanical ventilation, the presence of a recognized cause of ARDS, and the absence of clinical evidence of left-sided atrial hypertension.1 All patients had an arterial line for pressure monitoring and blood sampling.

Exclusion criteria included clinical instability as evidenced by changes in ventilator settings or medications within the preceding hour, the presence of left-sided ventricular dysfunction and/or left-sided atrial enlargement by cardiac echo, or previous left-sided heart catheterization, liver failure (Child-Pugh class B or C), renal failure on dialysis, thrombocytopenia, bleeding diathesis or active bleeding, asthma and/or severe bronchospasm, age < 18 years, and inability to obtain informed consent. For the first 10 patients, a systolic BP < 85 mm Hg or the need for pressors was a cause for exclusion. After review of the first 10 patients by the data safety monitoring board, patients taking norepinephrine (without additional pressors) were enrolled. This study was approved by the University of Oklahoma Health Sciences Center, institutional review board 3 (approval number 15123), listed in ClinicalTrials.gov (NCT01274481),16 and informed consent was obtained for all participants.

This was a 2.5-h study conducted on a single day in which each patient’s baseline measurements obtained prior to iloprost administration were compared with measurements obtained 30 min and 2 h after iloprost inhalation. While critically ill by virtue of their underlying illness, patients were clinically stable over the preceding 2 h prior to entry into the study as evidenced by airway pressures and arterial oxygen saturation that varied < 10% on the same ventilator settings. Ventilator settings including mode of ventilation, Fio2, tidal volume, and PEEP were not changed during the study.

At each study period, pulmonary mechanics were assessed by noting the peak and plateau airway pressures during mechanical ventilation. Oxygen consumption, CO2 production, and minute ventilation were measured with a Sensormedics metabolic cart (Sensormedics Corp).17 Gas exchange was monitored for ≥ 5 min, and once a steady state was reached, as evidenced by values that changed by < 10%, data from the last 3 min were averaged to establish baseline resting oxygen consumption, CO2 production, and minute ventilation. Blood for arterial blood gases (ABGs) was then drawn through the catheter for the measurement of pH, Pco2, and Po2 on an IStat blood gas machine (Abbott Laboratories).

The Pao2/Fio2 ratio was calculated from the measured Pao2 and the inspired oxygen concentration. The ventilatory equivalents for oxygen and CO2 were calculated as the minute ventilation divided by the oxygen consumption and CO2 production, respectively.

After baseline measurements were obtained, 10 μg iloprost was administered via an Aero Tech II nebulizer (Pharmalucence Inc) on the inspiratory line of the ventilator, which results in a delivered dose in the lung of 2.5 μg.18 The iloprost was nebulized in 1 mL saline over 5 min with an oxygen flow of 8 L/min. Vital sign measurements including BP, heart rate, respiratory rate, and arterial saturation by pulse oximetry were monitored at baseline and every 5 min after the inhalation of iloprost. Thirty minutes after the administration of iloprost, the gas exchange, pulmonary function, and ABG measurements were repeated as described previously. Patients received a second dose of iloprost, 20 μg in 2 mL saline, administered as for the first dose. Vital signs were monitored continuously; 30 min after the second dose of iloprost, all pulmonary measurements were repeated. Patients were monitored continuously for an additional 90 min after the second assessment of iloprost effects and pulmonary testing was repeated for a final time 2 h after the second administration of iloprost.

Statistical Methods

The primary outcome variable was the Pao2 as measured by the ABG. Secondary outcome variables analyzed were (1) Pao2/Fio2 ratio, (2) airway pressures, (3) lung compliance as measures of pulmonary mechanics, (4) the ventilatory equivalents for oxygen and CO2 as measures of gas exchange, and (5) heart rate and BP, which would reflect systemic effects of the inhaled iloprost.

Continuous data are expressed as mean (± SD) for normally distributed data or median (interquartile range [IQR]) for nonnormally distributed data. All comparisons were performed using repeated measures analysis of variance or rank-sum test for parametric and nonparametric data, respectfully. The sample size of 20 was chosen on the basis of our initial power analysis to provide an α of 0.05 with a power of 0.9 to detect a 20 mm Hg change in Pao2.

Results

The demographic characteristics of the 20 patients are summarized in Table 1. The median age was 59 years (IQR, 44-65 years), and pneumonia was the most common cause of ARDS, accounting for 14 cases; generalized sepsis and traumatic lung injury each accounted for three cases. All patients had echocardiographic evidence of PH, but only one had a PA catheter. Fourteen patients were ventilated in assist-control mode, and six were ventilated with synchronized intermittent mandatory ventilation. The median tidal volume was 5.7 mL/kg ideal body weight, and the median PEEP level was 6.5 cm H2O. One patient with a pneumothorax did not have PEEP applied. Baseline Pao2/Fio2 was 191 mm Hg (IQR, 121-222 mm Hg), and static respiratory system compliance was 31 mL/cm H2O (IQR, 25-38 mL/cm H2O). Most patients had mild (n = 9) or moderate (n = 8) ARDS, with only three having a baseline Pao2/Fio2 ratio < 100.

Effect on Gas Exchange

Nebulized iloprost produced a significant increase in Pao2 from 82 mm Hg to 100 mm Hg after the initial administration, and this improvement was maintained during the subsequent time periods (all P < .01) (Fig 1). It was still present 2 h after the second dose of iloprost had been administered. The increase in Pao2 was > 10 mm Hg in 18 of 20 patients. Only four patients who improved their Pao2 experienced a further increase of > 10 mm Hg after the second dose of iloprost. This improvement in oxygenation was associated with an improvement in the Pao2/Fio2 ratio (all P < .01). We observed a weak negative correlation between baseline Pao2/Fio2 ratio and improvement in Pao2 (r = −0.45; P < .05), suggesting the potential benefit on oxygenation was greater in those with more marked ARDS.

Figure Jump LinkFigure 1.Oxygenation: There were significant increases in Pao2 and the Pao2/Fio2 ratio after the administration of Ilo that persisted through the 2 h time period (*P < .01). Data expressed as mean (± SD). Ilo = iloprost.Grahic Jump Location

Minute ventilation remained relatively constant after iloprost administration, as did Paco2 (Fig 2). There was a small increase in oxygen consumption (P = .23), and a trend for the ventilatory equivalent for oxygen to fall, that failed to reach statistical significance (P = .06) (Fig 3).

Effect on Systemic Hemodynamics and Lung Mechanics

The administration of iloprost had no significant hemodynamic effect. Neither heart rate nor mean BP changed after the inhalation of iloprost (Fig 4). After data safety monitoring board review of the first 10 patients, eight of the last 10 patients enrolled were taking pressors during iloprost nebulization. None required an increase in the rate of pressor infusion after receiving iloprost.

Iloprost administration also had no significant effect on lung mechanics, as indicated by the lack of change in peak or plateau airway pressures (Fig 5). As expected in the absence of a change in airway pressures, there was no significant change in respiratory system compliance (data not shown).

Discussion

The present study demonstrates that nebulized iloprost produces a significant improvement in gas exchange as manifested by the increases in the Pao2 and Pao2/Fio2 ratio without any change in hemodynamics or lung mechanics. While previous studies have examined the effect of epoprostenol on Pao2 and hemodynamics in ARDS, this is the first study, to our knowledge, to look at iloprost in patients with ARDS and the first to examine the effect of an aerosolized prostacyclin derivative on pulmonary mechanics in patients with ARDS.

Previous studies have examined IV prostacyclin as potential therapy in patients with ARDS. Prostaglandin E1 (PGE1) can modulate neutrophil function and inhibit the release of proinflammatory mediators.19,20 PGE1 has been shown to reduce neutrophil aggregation and pulmonary capillary leak in animal models.21‐23 While a small, phase 2 trial of IV liposomal PGE1 observed a reduction in ventilator dependence,24 two subsequent studies of IV liposomal PGE1 failed to find a significant benefit. A European study observed no difference between patients in the treatment and placebo groups.25 Abraham et al26 noted that mechanical ventilation was discontinued more rapidly in those patients who received > 85% of the target dose. However, hypotension (52%) and hypoxemia (24%) were more common in the PGE1 group and necessitated stopping the infusion in 11% of those randomized to liposomal PGE1. The hypoxemia is a consequence of worsening V./Q. mismatching due to increased intrapulmonary shunt flow.27

In contrast to IV administration, several small studies have suggested that aerosolized prostacyclin may improve V./Q. matching. Walmrath et al28 found the effects of aerosolized prostacyclin were similar to those of an inhaled nitric oxide (NO). Both pulmonary vasodilators decreased shunt flow and increased Pao2. Zwissler and colleagues29 noted similar decreases in shunt and improvements in Pao2 after both NO and aerosolized PGI2 in eight patients with ARDS. van Heerden et al30 administered prostacyclin in escalating doses up to 50 μg/kg/min to nine patients with ARDS and found improvements in Pao2 and cardiac output without systemic hypotension. In the only randomized, placebo-controlled trial of aerosolized prostacyclin for ARDS, Dahlem et al31 noted improvement in Pao2 compared with saline placebo in eight of 14 children. None of these studies examined the effect of aerosolized prostacyclin on pulmonary mechanics.

The current study is the largest to use an aerosolized prostaglandin in patients with ARDS and the first to look at the effects of iloprost. We found the effects of iloprost on gas exchange were similar to that previously noted for epoprostenol. The improvement in the Pao2 and the Pao2/Fio2 ratio observed in these patients was similar to that observed with inhaled epoprostenol, and 18 of 20 patients had an increase in Pao2> 10 mm Hg. Equally important in treating the patient with severe lung disease, we observed no significant deleterious effect on pulmonary mechanics after iloprost administration. Peak and plateau pressures remained unchanged, as did lung compliance.

The pulmonary deposition of the iloprost doses administered in the present study, 10 μg and 20 μg via nebulizer, correspond to the 2.5-μg and 5.0-μg doses administered to patients with PAH. Most patients achieved an improved Pao2 with the first dose of iloprost and the second, high dose produced an improvement in only four patients. This suggests that the 10-μg dose produced maximal pulmonary vasodilation in the majority of patients. The benefit in Pao2 persisted 2 h after the second dose, which is consistent with iloprost’s mechanism of action. Although iloprost’s plasma half-life is relatively short (20-30 min), cyclic adenosine monophosphate (cAMP) levels may remain elevated for up to 4 h.32

Previous attempts to improve the outcome in the patients with ARDS with inhaled NO, a potent pulmonary vasodilator that acts via increasing cyclic guanosine monophosphate, have produced mixed results. Inhaled NO has been shown to produce immediate improvements in gas exchange in Pao2 in adults with ARDS.33,34 However, this beneficial effect is not sustained, and by 72 h there is no significant difference in Pao2.34 Most importantly, survival was not improved by NO administration.35 This diminution in the beneficial effect of NO may be due to the fact that NO also has proinflammatory activities and prolonged exposure can result in oxidative injury and the nitrosylation of proteins.36,37

In contrast, iloprost vasodilates by increasing cAMP levels. Increased cAMP might also be expected to reduce inflammation and enhance alveolar fluid reabsorption. The improvement we observed after iloprost administration was similar to that previously reported after NO administration. It remains to be determined if the beneficial effect of iloprost iloprost on oxygenation will be maintained over time. The present study indicates iloprost produces a rapid increase in Pao2 without adversely affecting hemodynamics or pulmonary mechanisms. Future studies will determine whether the beneficial effect of iloprost on oxygenation is sustained with repeated administration and accompanied by a reduction in biomarkers of lung injury.

Acknowledgments

Author contributions: Dr Kinasewitz had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Sawheny: contributed to data analysis and interpretation and writing the manuscript and served as principal author.

Ms Ellis: contributed to data analysis and interpretation and writing the manuscript.

Dr Kinasewitz: contributed to study conception and design, data analysis and interpretation, and drafting the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Kinasewitz has participated in clinical trials sponsored by Novartis AG, InterMune Inc, ALT Bioscience LLC, and Talecris Plasma Resources (Grifols Inc). All funds were paid to University of Oklahoma Health Sciences Center. The other authors declare no conflicts of interest.

Role of sponsor: The sponsor had no role in the study design, data interpretation, or manuscript preparation.

Figures

Figure Jump LinkFigure 1.Oxygenation: There were significant increases in Pao2 and the Pao2/Fio2 ratio after the administration of Ilo that persisted through the 2 h time period (*P < .01). Data expressed as mean (± SD). Ilo = iloprost.Grahic Jump Location

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